Harnessing the ubiquitin-proteasome system: advances and challenges of PROTACs in breast cancer

Breast cancer is one of the most significant health issues in the world, and resistance to treatment and a lack of targets that can be addressed with drugs limit the effectiveness of the existing treatment options. The development of proteolysis-targeting chimeras (PROTACs) has shifted the concept of occupancy-based inhibition toward event-based targeted protein degradation. Avoiding ubiquitin-proteasome hijacking, PROTACs target disease-relevant proteins to E3 ligases, allowing them to be catalytically degraded, thereby eliminating formerly undruggable or resistant targets. Their modular design, consisting of a warhead, linker, and E3 ligase ligand, eases rational design, but there are still difficulties, including hook effects, poor pharmacokinetics, and off-target toxicity. PROTACs have been known to undergo evolution, such as PHOTACs, CLIPTACs, and RIBOTACs, which have expanded therapeutic approaches. Clinical trial molecules such as ARV-471 have demonstrated an effective role in the degradation of ER+, showcasing their broader significance in HER2 by degrading BRD4, CDK, and PD-L1. However, a knowledge gap exists that limits our understanding of E3 ligases, constraining their tissue specificity and metabolism. Prospective directions focus on computational strategies to design E3 ligase-based PROTAC prodrugs, nanostructured PROTACs, and test them in vivo using organoids and xenograft models. Overall, PROTACs can become a novel therapeutic approach in the treatment of breast cancer.